tRF3-IleAAT reduced extracellular matrix synthesis in diabetic kidney disease mice by targeting ZNF281 and inhibiting ferroptosis.

It is well established that the synthesis of extracellular matrix (ECM) in mesangial cells is a major determinant of diabetic kidney disease (DKD). Elucidating the major players in ECM synthesis may be helpful to provide promising candidates for protecting against DKD progression. tRF3-IleAAT is a tRNA-derived fragment (tRF) produced by nucleases at tRNA-specific sites, which is differentially expressed in the sera of patients with diabetes mellitus and DKD. In this study we investigated the potential roles of tRFs in DKD. Db/db mice at 12 weeks were adapted as a DKD model. The mice displayed marked renal dysfunction accompanied by significantly reduced expression of tRF3-IleAAT and increased ferroptosis and ECM synthesis in the kidney tissues. The reduced expression of tRF3-IleAAT was also observed in high glucose-treated mouse glomerular mesangial cells. We administered ferrostatin-1 (1 mg/kg, once every two days, i.p.) to the mice from the age of 12 weeks for 8 weeks, and found that inhibition of the onset of ferroptosis significantly improved renal function, attenuated renal fibrosis and reduced collagen deposition. Overexpression of tRF3-IleAAT by a single injection of AAV carrying tRF3-IleAAT via caudal vein significantly inhibited ferroptosis and ECM synthesis in DKD model mice. Furthermore, we found that the expression of zinc finger protein 281 (ZNF281), a downstream target gene of tRF3-IleAAT, was significantly elevated in DKD models but negatively regulated by tRF3-IleAAT. In high glucose-treated mesangial cells, knockdown of ZNF281 exerted an inhibitory effect on ferroptosis and ECM synthesis. We demonstrated the targeted binding of tRF3-IleAAT to the 3'UTR of ZNF281. In conclusion, tRF3-IleAAT inhibits ferroptosis by targeting ZNF281, resulting in the mitigation of ECM synthesis in DKD models, suggesting that tRF3-IleAAT may be an attractive therapeutic target for DKD.

Effects and Mechanisms of Transcutaneous Electrical Acustimulation on Postoperative Recovery After Elective Cesarean Section.

OBJECTIVES: To explore the effects and mechanisms of transcutaneous electrical acustimulation (TEA) on postoperative recovery after cesarean section (CS). MATERIALS AND METHODS: A total of 108 women who underwent CS were randomized to receive TEA or sham-TEA. Four hours after CS, electrogastrogram (EGG) and electrocardiogram (ECG) were recorded for 30 min to assess gastric slow waves and autonomic functions, respectively. TEA at ST36 or sham-TEA at non-acupoints was performed for one hour right after recording ECG and EGG and then twice daily from postoperative days (POD) 1 to 3. In the morning of POD4, the EGG and ECG were recorded again for 30 min. RESULTS: TEA enhanced postoperative recovery associated with lower GI motility, reflected as a reduction in time of first flatus (p = 0.002) and time of first defecation (p < 0.001), an increase in the Bristol stool score (p < 0.001) and the number of SBMs (p < 0.001) in comparison with sham-TEA. TEA reduced symptoms associated with upper GI motility, including a reduction in time to resume semifluid (p = 0.008), and the total score of loss of appetite (p = 0.003) and belching (p = 0.038) from POD1 to POD3. Physiologically, TEA but not sham-TEA increased the percentage of normal gastric slow waves on POD4 compared with POD0 (p = 0.001). TEA reduced the visual analogue scale (VAS) pain score from POD1 to POD3 (p < 0.001). TEA but not sham-TEA increased vagal activity (p = 0.013) and decreased sympathetic activity (p = 0.013) on POD4 compared with POD0. Two factors were found to be independent predictors of shortened time of the first defecation: the use of TEA and a shorter surgical duration. CONCLUSIONS: Needleless non-invasive TEA at ST36 is effective in promoting both lower and upper GI symptoms after CS by enhancing vagal and suppressing sympathetic activities [Correction added on 23 June 2020, after first online publication: The first word of the preceded sentence has been corrected.].

Phyllanthin and hypophyllanthin from Phyllanthus amarus ameliorates immune-inflammatory response in ovalbumin-induced asthma: role of IgE, Nrf2, iNOs, TNF-α, and IL's.

Background: Asthma is a chronic airway immunoinflammatory disorder characterized by airway remodeling. Phyllanthus amarus has been reported to possess antioxidant and anti-inflammatory potential. Aim: To evaluate the possible mechanism of action of isolated phytoconstituents from P. amarus (PA) against ovalbumin (OVA)-induced experimental airway hyperresponsiveness (AHR). Material and method: Phyllanthin and hypophyllanthin were isolated and characterized (HPLC) from the methanolic extract of PA. AHR was induced in Sprague-Dawley rats by OVA-challenged, and animals were treated with PA (50, 100, and 200 mg/kg, p.o.) for 28 days. Results: The HPLC analysis showed the presence of phyllanthin and hypophyllanthin in methanolic extract of PA at RT of 25.243 and 26.832 min, respectively. OVA-induced alterations in hemodynamic parameters, lung functions test, peripheral blood oxygen level, total, and differential cell count in Bronchoalveolar Lavage Fluid was significantly attenuated (p < .05) by PA (100 and 200 mg/kg). It also significantly decreased (p < .05) the levels of total protein and albumin in serum, BALF, and lungs. OVA-induced increase in IgE (total and OVA-specific), and oxido-nitrosative stress (SOD, GSH, MDA, and NO) levels were significantly (p < .05) decreased by PA. RT-PCR analysis revealed that elevated oxido-nitrosative stress (Nrf2 and iNOs), immune-inflammatory makers (HO-1, TNF-α, IL-1ß, and TGF-ß1), Th2 cytokines (IL-4 and IL-6) levels were significantly attenuated (p < .05) by PA. PA also attenuated histological and ultrastructural aberrations induced by OVA. Conclusion: Results of the present investigation demonstrated that the presence of phyllanthin and hypophyllanthin in P. amarus alleviated Th2 response in OVA-induced AHR via modulation of endogenous markers in a murine model of asthma. Thus, phyllanthin and hypophyllanthin may be a new therapeutic approach for the management of asthma.

Effect of Syringic acid on antioxidant biomarkers and associated inflammatory markers in mice model of asthma.

Asthma is termed as the induction of chronic inflammation in the airway lumen of lungs due to accumulation of inflammatory cells which affects normal breathing process. Prolonged accumulation of inflammatory cells leads to oxidative stress and suppression of antioxidant activities. Therefore, in our present investigation, a potential phenolic compound, Syringic acid was tested for the suppression of inflammatory markers toward an antiasthmatic activity in ovalbumin (OVA)-induced asthmatic mice model. As a result, the Syringic acid treatment was found to suppress the inflammatory cells; eosinophil, neutrophil, macrophage, lymphocyte, and other inflammatory markers including IL-4, IL-5, IL-13, and TNF-α in the BALF of OVA-induced asthmatic mice. Similarly, IgE levels were significantly reduced in the blood serum of Syringic acid treated mice groups. In this context, the IFN-γ levels were found enhanced in the BALF of Syringic acid treated asthmatic mice groups, expressing an anti-inflammatory response. Enzymatic and nonenzymatic antioxidants such as SOD, CAT, and GSH levels were found high in the Syringic acid treatment than the asthmatic control group, which depicts the antioxidant response of Syringic acid on asthmatic groups. Intriguingly, the ROS, NO2 , NO3 , and MDA levels were inhibited in the BALF of Syringic acid treated mice groups. The airway hyper-reactivity (AHR) was comparatively normal in the Syringic acid treatment as it was severe in the case of asthmatic control group. Consequently, the effect of Syringic acid is prominent in the treatment of asthma by controlling the accumulation of inflammatory cells, other inflammatory markers along with enhancement of antioxidant markers, suppression of ROS and controlling airway hyperreactivity. Hence, Syringic acid may be recommended for clinical trials in the treatment of asthma.

Diversity and potential host-interactions of viruses inhabiting deep-sea seamount sediments.

Seamounts are globally distributed across the oceans and form one of the major oceanic biomes. Here, we utilized combined analyses of bulk metagenome and virome to study viral communities in seamount sediments in the western Pacific Ocean. Phylogenetic analyses and the protein-sharing network demonstrate extensive diversity and previously unknown viral clades. Inference of virus-host linkages uncovers extensive interactions between viruses and dominant prokaryote lineages, and suggests that viruses play significant roles in carbon, sulfur, and nitrogen cycling by compensating or augmenting host metabolisms. Moreover, temperate viruses are predicted to be prevalent in seamount sediments, which tend to carry auxiliary metabolic genes for host survivability. Intriguingly, the geographical features of seamounts likely compromise the connectivity of viral communities and thus contribute to the high divergence of viral genetic spaces and populations across seamounts. Altogether, these findings provides knowledge essential for understanding the biogeography and ecological roles of viruses in globally widespread seamounts.

Identification of Immune-Related Genes for Establishment of Prognostic Index in Hepatocellular Carcinoma.

Background: Immune checkpoint inhibitor (ICI) therapy has been proved to be a promising therapy to many types of solid tumors. However, effective biomarker for estimating the response to ICI therapy and prognosis of hepatocellular carcinoma (HCC) patients remains underexplored. The aim of this study is to build a novel immune-related prognostic index based on transcriptomic profiles. Methods: Weighted gene co-expression network analysis (WGCNA) was conducted to identify immune-related hub genes that are differentially expressed in HCC cohorts. Next, univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) analysis were used to detect hub genes associated to overall survival (OS). To validate the immune-related prognostic index, univariate and multivariate Cox regression analysis were performed. CIBERSORT and ESTIMATE were used to explore the tumor microenvironment and immune infiltration level. Results: The differential expression analysis detected a total of 148 immune-related genes, among which 25 genes were identified to be markedly related to overall survival in HCC patients. LASSO analysis yielded 10 genes used to construct the immune-related gene prognostic index (IRGPI), by which a risk score is computed to estimate low vs. high risk indicating the response to ICI therapy and prognosis. Further analysis confirmed that this immune-related prognostic index is an effective indicator to immune infiltration level, response to ICI treatment and OS. The IRGPI low-risk patients had better overall survival (OS) than IRGPI high-risk patients on two independent cohorts. Moreover, we found that IRGPI high-risk group was correlated with high TP53 mutation rate, immune-suppressing tumor microenvironment, and these patients acquired less benefit from ICI therapy. In contrast, IRGPI-low risk group was associated with low TP53 and PIK3CA mutation rate, high infiltration of naive B cells and T cells, and these patients gained relatively more benefit from ICI therapy.

[Serum levels of IL-13 and TNF-alpha in children with Mycoplasma pneumoniae pneumonia].

OBJECTIVE: To examine serum levels of interleukin-13 (IL-13) and tumor necrosis factor alpha (TNF-alpha) in children with Mycoplasma pneumoniae (MP) pneumonia. METHODS: Eighty children with MP pneumonia complicated by wheezing or without (n=40 each), 40 children with pneumonia from non-MP infection and 40 healthy children were enrolled. Serum levels of IL-13 and TNF-alpha were measured using ELISA. RESULTS: The serum levels of IL-13 and TNF-alpha in the MP pneumonia group were significantly higher than those in non-MP pneumonia group and the healthy control group (P<0.01). The children with MP pneumonia complicated by wheezing had increased serum levels of IL-13 (214.6 + or - 67.2 ng/L vs 189.6 + or - 52.1 ng/L; P<0.01) and TNF-alpha(0.55 + or - 0.13 ng/mL vs 0.42 + or - 0.16 ng/mL; P<0.01)compared with those without wheezing. CONCLUSIONS: The increase in serum levels of IL-13 and TNF-alpha may play important roles in the pathogenesis of MP pneumonia and wheezing attack in children.

Identification of lncRNA-mRNA Regulatory Module to Explore the Pathogenesis and Prognosis of Melanoma.

Skin cutaneous melanoma (SKCM) is an aggressive form of skin cancer that results in high mortality rate worldwide. It is vital to discover effective prognostic biomarkers and therapeutic targets for the treatment of melanoma. Long non-coding RNA (lncRNA) has been verified to play an essential role in the regulation of gene expression in diseases and tumors. Therefore, it is significant to explore the function of lncRNAs in the development and progression of SKCM. In this paper, a set of differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were first screened out using 471 cutaneous melanoma samples and 813 normal skin samples. Gene Ontology and KEGG pathway enrichment analysis were performed to obtain the significant function annotations and pathways of DEmRNAs. We also ran survival analysis on both DElncRNAs and DEmRNAs to identify prognostic-related lncRNAs and mRNAs. Next, a set of hub genes derived from protein-protein interaction (PPI) network analysis and lncRNA target genes screened from starbase-ENCORI database were integrated to construct a lncRNA-mRNA regulatory module, which includes 6 lncRNAs 4 target mRNAs. We further checked the capacity of these lncRNA and mRNA in the diagnosis of melanoma, and found that single lncRNA can effectively distinguish tumor and normal tissue. Moreover, we ran CMap analysis to select a list of small molecule drugs for SKCM, such as EGFR inhibitor AG-490, growth factor receptor inhibitor GW-441756 and apoptosis stimulant betulinic-acid, which have shown therapeutic effect in the treatment of melanoma.

Association of serum 25-hydroxyvitamin D status with bone mineral density in 0-7 year old children.

OBJECTIVE: To describe the status of serum 25-hydoxyvitamin D [25(OH)D] concentrations and identify the relationship between 25(OH)D and bone mineral density (BMD). In an effort to explore the appropriate definition of vitamin D (VD) deficiency in 0-7 year old children. RESULTS: The median serum 25(OH)D concentrations was 62.9 nmol/L and 28.9% of the children had a low 25(OH)D (< 50 nmol/L). And a linear relation between 25(OH)D concentrations and BMD was surveyed (r = 0.144 , P < 0.001). After adjusting for the confounders, serum 25(OH)D was positively associated with BMD (ß = 172.0, 95%CI = 142.8-201.2, P < 0.001), and low 25(OH)D (< 75 nmol/L) had a high stake for low BMD (OR = 1.424, 95%CI = 1.145-1.769, P = 0.001). Additionally, there was a nonlinear relation between 25(OH)D and low BMD, and a critical value for 25(OH)D of 75 nmol/L appeared for low BMD. The prevalence of low BMD was 14.1% in children with 25(OH)D ≥ 75 nmol/L, much lower than that of the concentrations between 50-75 nmol/L and < 50 nmol/L. MATERIALS AND METHODS: A total of 4,846 children 0-7 years old were recruited in Jiangsu Province, China. BMD and serum 25(OH)D concentrations were determined by quantitative ultrasound and enzyme-linked immunosorbent assay, respectively. Linear regression and logistic regression analyses were used to assess the association of 25(OH)D concentrations with BMD. CONCLUSIONS: Serum 25(OH)D concentrations was related with BMD and 25(OH)D concentrations < 75 nmol/L might be a more appropriate definition of VD deficiency in 0-7 year old children.